. 2022 Jun;54(6):761-771.

doi: 10.1038/s41588-022-01078-z. Epub 2022 Jun 2.

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Marijana Vujkovic^#^{1

2}, Shweta Ramdas^#³, Kim M Lorenz^{1

3

4}, Xiuqing Guo⁵, Rebecca Darlay⁶, Heather J Cordell⁶, Jing He⁷, Yevgeniy Gindin⁸, Chuhan Chung⁸, Robert P Myers^{8

9}, Carolin V Schneider³, Joseph Park^{2

3}, Kyung Min Lee¹⁰, Marina Serper^{1

2}, Rotonya M Carr¹¹, David E Kaplan^{1

2}, Mary E Haas¹², Matthew T MacLean³, Walter R Witschey¹³, Xiang Zhu^{14

15

16

17}, Catherine Tcheandjieu^{14

18}, Rachel L Kember^{19

20}, Henry R Kranzler^{19

20}, Anurag Verma^{1

3}, Ayush Giri²¹, Derek M Klarin^{14

22

23}, Yan V Sun^{24

25}, Jie Huang²⁶, Jennifer E Huffman²⁷, Kate Townsend Creasy³, Nicholas J Hand³, Ching-Ti Liu²⁸, Michelle T Long²⁹, Jie Yao⁵, Matthew Budoff³⁰, Jingyi Tan⁵, Xiaohui Li⁵, Henry J Lin⁵, Yii-Der Ida Chen⁵, Kent D Taylor⁵, Ruey-Kang Chang⁵, Ronald M Krauss³¹, Silvia Vilarinho³², Joseph Brancale³², Jonas B Nielsen³³, Adam E Locke³³, Marcus B Jones³³, Niek Verweij³³, Aris Baras³³, K Rajender Reddy², Brent A Neuschwander-Tetri³⁴, Jeffrey B Schwimmer³⁵, Arun J Sanyal³⁶, Naga Chalasani³⁷, Kathleen A Ryan³⁸, Braxton D Mitchell³⁸, Dipender Gill³⁹, Andrew D Wells^{40

41}, Elisabetta Manduchi³, Yedidya Saiman⁴², Nadim Mahmud⁴³, Donald R Miller^{44

45}, Peter D Reaven^{46

47}, Lawrence S Phillips^{24

48}, Sumitra Muralidhar⁴⁹, Scott L DuVall^{10

50}, Jennifer S Lee^{14

18}, Themistocles L Assimes^{14

18

51}, Saiju Pyarajan^{27

52

53}, Kelly Cho^{27

52

53}, Todd L Edwards^{54

55}, Scott M Damrauer^{1

3

56}, Peter W Wilson^{24

57}, J Michael Gaziano^{27

52}, Christopher J O'Donnell^{27

52

53}, Amit V Khera^{23

53

58}, Struan F A Grant^{3

59

60}, Christopher D Brown³, Philip S Tsao^{14

18

51}, Danish Saleheen^{61

62

63}, Luca A Lotta³³, Lisa Bastarache⁷, Quentin M Anstee^{64

65}, Ann K Daly⁶⁵, James B Meigs^{23

53

66}, Jerome I Rotter⁵, Julie A Lynch^{10

50

67}; Regeneron Genetics Center; Geisinger-Regeneron DiscovEHR Collaboration; EPoS Consortium; VA Million Veteran Program; Daniel J Rader^#^{2

3}, Benjamin F Voight^#^{68

69

70

71}, Kyong-Mi Chang^#^{72

73}

Affiliations

¹ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
² Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶ Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Gilead Sciences, Inc., Foster City, CA, USA.
⁹ The Liver Company, Palo Alto, CA, USA.
¹⁰ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹¹ Division of Gastroenterology, University of Washington, Seattle, WA, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁵ Department of Statistics, The Pennsylvania State University, University Park, PA, USA.
¹⁶ Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
¹⁷ Department of Statistics, Stanford University, Stanford, CA, USA.
¹⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Mental Illness Research Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
²⁰ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²¹ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Division of Vascular Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
²³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Atlanta VA Medical Center, Decatur, GA, USA.
²⁵ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
²⁶ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
²⁷ VA Boston Healthcare System, Boston, MA, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁹ Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.
³⁰ Department of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³¹ Departments of Pediatrics and Medicine, University of California, San Francisco, San Francisco, CA, USA.
³² Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
³³ Regeneron Genetics Center, Tarrytown, NY, USA.
³⁴ Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA.
³⁵ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
³⁶ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
³⁷ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁸ Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁴⁰ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴¹ Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴² Department of Medicine, Section of Hepatology, Lewis Katz School of Medicine at Temple University, Temple University Hospital, Philadelphia, PA, USA.
⁴³ Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴⁴ Center for Healthcare Organization and Implementation Research, Bedford VA Healthcare System, Bedford, MA, USA.
⁴⁵ Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA.
⁴⁶ Phoenix VA Health Care System, Phoenix, AZ, USA.
⁴⁷ College of Medicine, University of Arizona, Phoenix, AZ, USA.
⁴⁸ Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
⁴⁹ Office of Research and Development, Veterans Health Administration, Washington, DC, USA.
⁵⁰ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵¹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁵² Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
⁵³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁵⁴ Nashville VA Medical Center, Nashville, TN, USA.
⁵⁵ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵⁷ Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
⁵⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵⁹ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶⁰ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁶² Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
⁶³ Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
⁶⁴ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶⁵ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷ College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
⁶⁸ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁶⁹ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷¹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷² Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. kmchang@pennmedicine.upenn.edu.
⁷³ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. kmchang@pennmedicine.upenn.edu.

^# Contributed equally.

PMID: 35654975
PMCID: PMC10024253
DOI: 10.1038/s41588-022-01078-z

A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Marijana Vujkovic et al. Nat Genet. 2022 Jun.

. 2022 Jun;54(6):761-771.

doi: 10.1038/s41588-022-01078-z. Epub 2022 Jun 2.

Authors

Affiliations

¹ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
² Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶ Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Gilead Sciences, Inc., Foster City, CA, USA.
⁹ The Liver Company, Palo Alto, CA, USA.
¹⁰ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹¹ Division of Gastroenterology, University of Washington, Seattle, WA, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁵ Department of Statistics, The Pennsylvania State University, University Park, PA, USA.
¹⁶ Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, USA.
¹⁷ Department of Statistics, Stanford University, Stanford, CA, USA.
¹⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Mental Illness Research Education and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
²⁰ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²¹ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
²² Division of Vascular Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
²³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Atlanta VA Medical Center, Decatur, GA, USA.
²⁵ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
²⁶ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
²⁷ VA Boston Healthcare System, Boston, MA, USA.
²⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
²⁹ Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.
³⁰ Department of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³¹ Departments of Pediatrics and Medicine, University of California, San Francisco, San Francisco, CA, USA.
³² Section of Digestive Diseases, Department of Internal Medicine, and Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
³³ Regeneron Genetics Center, Tarrytown, NY, USA.
³⁴ Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA.
³⁵ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
³⁶ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
³⁷ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁸ Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁴⁰ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴¹ Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴² Department of Medicine, Section of Hepatology, Lewis Katz School of Medicine at Temple University, Temple University Hospital, Philadelphia, PA, USA.
⁴³ Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴⁴ Center for Healthcare Organization and Implementation Research, Bedford VA Healthcare System, Bedford, MA, USA.
⁴⁵ Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA.
⁴⁶ Phoenix VA Health Care System, Phoenix, AZ, USA.
⁴⁷ College of Medicine, University of Arizona, Phoenix, AZ, USA.
⁴⁸ Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
⁴⁹ Office of Research and Development, Veterans Health Administration, Washington, DC, USA.
⁵⁰ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁵¹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁵² Department of Medicine, Brigham Women's Hospital, Boston, MA, USA.
⁵³ Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁵⁴ Nashville VA Medical Center, Nashville, TN, USA.
⁵⁵ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁵⁷ Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
⁵⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵⁹ Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶⁰ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁶¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁶² Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
⁶³ Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
⁶⁴ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶⁵ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶⁶ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷ College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
⁶⁸ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁶⁹ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷⁰ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷¹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. bvoight@pennmedicine.upenn.edu.
⁷² Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. kmchang@pennmedicine.upenn.edu.
⁷³ Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. kmchang@pennmedicine.upenn.edu.

^# Contributed equally.

PMID: 35654975
PMCID: PMC10024253
DOI: 10.1038/s41588-022-01078-z

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P < 5 × 10^-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n = 44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P < 6.5 × 10^-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.

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Conflict of interest statement

Competing interests

H.R.K. is a scientific advisory board member for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals and Enthion Pharmaceuticals; a consultant for Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi and Otsuka; and is named as an inventor on the Patent Cooperation Treaty patent application #15/878,640 entitled ‘Genotype-guided dosing of opioid agonists,’ filed 24 January 2018. D.G. is employed part-time by Novo Nordisk. A.V.K. is an employee and holds equity in Verve Therapeutics; has served as a scientific advisor to Amgen, Third Rock Ventures, Illumina, and Foresite Labs; received a sponsored research agreement from IBM Research; and is listed as a co-inventor on a patent application for use of imaging data in assessing body fat distribution and associated cardiometabolic risk. S.J.A. is President of Sanyal Bio; has stock options in Genfit, Galmed, Exhalenz, Durect, Tiziana, Algernon and Indalo; has served as a consultant to Intercept, Gilead, Bristol Myers Squibb, Novartis, Pfizer, Lilly, Novo Nordisk, AstraZeneca, Medimmune, Merck, Allergan, Albireo, Boehringer Ingelhiem, Celgene, NGM, Glympse, Conatus, Genentech, Tern, Takeda, Hemoshear, Immuron, Surrozen, Poxel, Path AI, Second Genome, Zydus, Chiasma, Surrozen, Poxel, Blade, Pliant, Liposcience, Cymabay, Salix, Ferring and Teva; and his institution has received grants from Intercept, Gilead, Novartis, Merck, AstraZeneca, Malinckrodt, Pfizer, Lilly, Salix and Bristol Myers Squibb. V.C.U. has ownership interests in Sanyal Bio. K.R.R. is on the NASH Advisory Board at Novo Nordisk and receives grant support from TARGET-NASH, Bristol Myers Squibb and Intercept Pharmaceuticals. J.B.N., A.E.L., M.B.J., N.V., A.B., M.E.H. and L.A.L. receive salary, stocks and/or stock options from Regeneron Pharmaceuticals. R.P.M. and C.C. are employees and shareholders of Gilead Sciences. Q.M.A. is coordinator of the EU IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 program and the European Federation of Pharmaceutical Industries and Associations. Q.M.A. reports research grant funding from Allergan/Tobira, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Glympse Bio, Intercept, Novartis Pharma and Pfizer; Consultancy for 89Bio, Abbvie/Allergan, Akero, Altimentiv, Altimmune, AstraZeneca, Axcella, Blade, BMS, BNN Cardio, Boehringer Ingelheim, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company, Galmed, Genentech, Genfit, Gilead, Grunthal, HistoIndex, Indalo, Intercept Pharma, Inventiva, IQVIA, Janssen, Johnson & Johnson, Madrigal, MedImmune, Medpace, Merck, Metacrine, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, ProSciento, Raptor Pharma, Roche, Servier, Shionogi, Terns, The Medicines Company and Viking Therapeutics; speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit, Gilead, Integritas Communications, Kenes and Medscape; and royalties from Elsevier. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs outside the scope of the current research. S.L.D. reports grants from Alnylam Pharmaceuticals, Astellas Pharma, AstraZeneca Pharmaceuticals, Biodesix, Boehringer Ingelheim International, Celgene Corporation, Eli Lilly and Company, Genentech, Gilead Sciences, GlaxoSmithKline, Innocrin Pharmaceuticals, IQVIA, Janssen Pharmaceuticals, Kantar Health, MDxHealth, Merck & Co, Myriad Genetic Laboratories, Novartis International and Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. C.J.O. is an employee of Novartis Institute for Biomedical Research. S.F.A.G. is the Daniel B. Burke Endowed Chair for Diabetes Research. The remaining authors declare no competing interests.

Figures

**Fig. 1 |. Overview of analysis pipeline.**
The flow diagram shows in the red box our study design with initial inclusion of 430,400 MVP participants with genotyping and ancestry classification by HARE, exclusion of individuals with known liver disease or alcohol dependence and inclusion of participants based on cALT (case) or normal ALT (control). This resulted in 90,408 proxy NAFLD cases and 128,187 controls with EA, AA, HISP and ASN ancestries that were examined in primary multiancestry and ancestry-specific genome-wide association scans. The orange box of the flow diagram highlights our results of multiancestry and ancestry-specific meta-analyses identifying 77 multiancestry loci + 1 EA-specific locus + 2 AA-specific loci that met genome-wide significance. The green box summarizes the results from external replication cohorts, whereas the blue box indicates all the post-GWAS annotation analyses that we performed, which include secondary signal analysis, fine-mapping (95% credible sets), (tissue-specific) heritability estimation, genetic correlations analysis, variant-to-gene-mapping and pleiotropy analysis. ATAC-seq, assay for transposase-accessible chromatin with high-throughput sequencing; FHS, Framingham Heart Study; GRS, genetic risk score; MESA, Multi-Ethnic Study of Atherosclerosis; NASH-CRN, Non-Alcoholic Steatohepatitis Clinical Research Network; PMBB, Penn Medicine Biobank; PPI, protein–protein interaction; QTL, quantitative trait locus; UKBB, UK Biobank; HARE, harmonized ancestry and race/ethnicity; BioVU, the DNA databank at Vanderbilt; Regeneron/DiscovEHR, collaboration between the Regeneron Genetics Center and Geisinger Health System; DEPICT, data-driven expression prioritized integration for complex traits; ldhub, a centralized database and web interface to perform LD score regression; Amish, University of Maryland Old Order Amish Study.

**Fig. 2 |. Manhattan plot of GWAS of 90,408 cALT cases and 128,187 controls in multiancestry meta-analysis.**
Nominated genes are indicated for 77 loci reaching genome-wide significance (P < 5 × 10⁻⁸). Previously reported NAFLD loci with genome-wide significant association are indicated in green font. Red asterisks indicate the SNPs that have been replicated with liver biopsy and/or radiologic imaging.

**Fig. 3 |. Venn diagram depicting overlapping liver, metabolic and inflammatory traits among cALT-associated loci.**
Overlapping liver (black), metabolic (purple) and/or inflammatory (green) traits are shown in association with 77 multiancestry and additional ancestry-specific lead SNPs. The trait categorizations reflect significant SNP–trait associations identified by (1) LabWAS of clinical laboratory results in MVP, (2) PheWAS with UK Biobank data using SAIGE, (3) SNP lookup using the curated data in the IEU OpenGWAS projects and (4) cross-trait colocalization analyses using colocalization analysis in EA, AA and HISP lead loci with 36 other GWAS statistics of cardiometabolic and blood cell-related traits. Genes denoted in bold and color-coded in red refer to the loci also associated with qHF on imaging analyses or histologically characterized NAFLD from liver biopsies. *Locus identified in European-only GWAS. **Locus identified in AA-restricted analysis. +Secondary signal from EA analysis (e.g., *HNF1A*/*P2RX7*).

**Fig. 4 |. Seven gene clusters with distinct biomarker association profiles.**
The 77 loci cluster along seven groups using stratified linkage hierarchical clustering. Each cluster has a distinct biomarker association profile, which is visualized with a heatmap. The 26 traits are clustered within their biological strata (e.g., lipids, inflammation, metabolic and liver). The color coding corresponds to the direction of association of the cALT-increasing allele (red, positive association; blue, negative association) and the strength of the association based on the P value. DBP, diastolic blood pressure; SBP, systolic blood pressure; T2D, type 2 diabetes; GLU, glucose; HbA1c, hemoglobin A1c; LYM, lymphocyte count; MONO, monocyte count; CRP, C-reactive protein; EOS, eosinophil count; GRANU, granulocyte count; WBC, white blood cell count; NEU, neutrophil count; SHBG, sex hormone binding globulin; ApoA-1, apolipoprotein A1; TRIG, triglycerides; ApoB-1, apolipoprotein B1; TCHOL, total cholesterol.

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Ghouse J, Sveinbjörnsson G, Vujkovic M, Seidelin AS, Gellert-Kristensen H, Ahlberg G, Tragante V, Rand SA, Brancale J, Vilarinho S, Lundegaard PR, Sørensen E, Erikstrup C, Bruun MT, Jensen BA, Brunak S, Banasik K, Ullum H; DBDS Genomic Consortium; Verweij N, Lotta L, Baras A; Regeneron Genetics Center; Mirshahi T, Carey DJ; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program; Kaplan DE, Lynch J, Morgan T, Schwantes-An TH, Dochtermann DR, Pyarajan S, Tsao PS; Estonian Biobank Research Team; Laisk T, Mägi R, Kozlitina J, Tybjærg-Hansen A, Jones D, Knowlton KU, Nadauld L, Ferkingstad E, Björnsson ES, Ulfarsson MO, Sturluson Á, Sulem P, Pedersen OB, Ostrowski SR, Gudbjartsson DF, Stefansson K, Olesen MS, Chang KM, Holm H, Bundgaard H, Stender S. Ghouse J, et al. Nat Genet. 2024 May;56(5):827-837. doi: 10.1038/s41588-024-01720-y. Epub 2024 Apr 17. Nat Genet. 2024. PMID: 38632349 Free PMC article.

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References

1. Asrani SK, Devarbhavi H, Eaton J & Kamath PS Burden of liver diseases in the world. J. Hepatol 70, 151–171 (2019). - PubMed
1. Younossi Z, Anstee QM & Marietti M Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol 15, 11–20 (2018). - PubMed
1. Estes C, Razavi H, Loomba R, Younossi Z & Sanyal AJ Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 67, 123–133 (2018). - PMC - PubMed
1. Carr RM, Oranu A & Khungar V Nonalcoholic fatty liver disease: pathophysiology and management. Gastroenterol. Clin. North Am 45, 639–652 (2016). - PMC - PubMed
1. Chalasani N et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018). - PubMed

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A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

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A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

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